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Helminth Infection Does Not Reduce Risk for Chronic Inflammatory Disease in a Population-Based Cohort Study

Published:October 07, 2011DOI:https://doi.org/10.1053/j.gastro.2011.09.046

      Background & Aims

      Parasitic helminth infections can suppress symptoms of allergy, type 1 diabetes, arthritis, and inflammatory bowel disease in animal models. We analyzed data from a large, population-based cohort study to determine whether common childhood enterobiasis protects against these diseases.

      Methods

      We collected information on individual prescriptions filled for the drug Mebendazole against Enterobius vermicularis for all children born in Denmark 1995–2008 from the National Register of Medicinal Product Statistics (n = 924,749; age 0–14 years); 132,383 of these children (14%) filled a prescription for Mebendazole, 102,482 of the children (11%) had a household peer who was registered with a filled Mebendazole prescription, and the remaining 689,884 children (75%) comprised the reference group. Children diagnosed with asthma, type 1 diabetes, juvenile arthritis, ulcerative colitis, or Crohn's disease were identified from the National Patient Registry. We used Poisson regression to estimate confounder-adjusted incidence rate ratios for first in- or outpatient hospital diagnosis of chronic inflammatory disease according to history of Mebendazole treatment prescribed to children in the study.

      Results

      Chronic inflammatory disease was diagnosed in 10,352 children during 6.4 million person-years of follow-up. The incidence rate ratios was 1.07 for asthma (95% confidence interval [CI]: 1.00–1.13), 1.05 for type 1 diabetes (95% CI: 0.79–1.12), 1.13 for juvenile arthritis (95% CI: 0.94–1.37), 0.77 for ulcerative colitis (95% CI: 0.41–1.46), and 1.44 for Crohn's disease (95% CI: 0.82–2.53). Results were not modified by number of treatments or age at treatment.

      Conclusions

      Based on a population-based analysis, enterobiasis does not reduce risk for asthma, type 1 diabetes, arthritis, or inflammatory bowel disease.

      Keywords

      Abbreviations used in this paper:

      CI (confidence interval), GP (general practitioner), ICD (International Classification of Diseases), IRR (incidence rate ratios)
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      References

        • Weinstock J.V.
        • Elliott D.E.
        Helminths and the IBD hygiene hypothesis.
        Inflamm Bowel Dis. 2009; 15: 128-133
        • Schubert C.
        The worm has turned.
        Nat Med. 2004; 10: 1271-1272
        • Wickelgren I.
        Immunotherapy.
        Science. 2004; 305: 171
        • Wickelgren I.
        Immunotherapy.
        Science. 2004; 305: 170-171
        • Summers R.W.
        • Elliott D.E.
        • Urban Jr, J.F.
        • et al.
        Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial.
        Gastroenterology. 2005; 128: 825-832
        • Summers R.W.
        • Elliott D.E.
        • Urban Jr, J.F.
        • et al.
        Trichuris suis therapy in Crohn's disease.
        Gut. 2005; 54: 87-90
        • Feary J.R.
        • Venn A.J.
        • Mortimer K.
        • et al.
        Experimental hookworm infection: a randomized placebo-controlled trial in asthma.
        Clin Exp Allergy. 2010; 40: 299-306
        • Bager P.
        • Arnved J.
        • Ronborg S.
        • et al.
        Trichuris suis ova therapy for allergic rhinitis: a randomized, double-blind, placebo-controlled clinical trial.
        J Allergy Clin Immunol. 2010; 125: 123-130
        • Smits H.H.
        • Hammad H.
        • van Nimwegen M.
        • et al.
        Protective effect of Schistosoma mansoni infection on allergic airway inflammation depends on the intensity and chronicity of infection.
        J Allergy Clin Immunol. 2007; 120: 932-940
        • Wilson M.S.
        • Taylor M.D.
        • Balic A.
        • et al.
        Suppression of allergic airway inflammation by helminth-induced regulatory T cells.
        J Exp Med. 2005; 202: 1199-1212
        • Mangan N.E.
        • Fallon R.E.
        • Smith P.
        • et al.
        Helminth infection protects mice from anaphylaxis via IL-10-producing B cells.
        J Immunol. 2004; 173: 6346-6356
        • Mangan N.E.
        • Van Rooijen N.
        • McKenzie A.N.
        • et al.
        Helminth-modified pulmonary immune response protects mice from allergen-induced airway hyperresponsiveness.
        J Immunol. 2006; 176: 138-147
        • Espinoza-Jimenez A.
        • Rivera-Montoya I.
        • Cardenas-Arreola R.
        • et al.
        Taenia crassiceps infection attenuates multiple low-dose streptozotocin-induced diabetes.
        J Biomed Biotechnol. 2009; 2010 (Article ID 850541, 11 pages)https://doi.org/10.1155/2010/850541
        • Hubner M.P.
        • Stocker J.T.
        • Mitre E.
        Inhibition of type 1 diabetes in filaria-infected non-obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells.
        Immunology. 2009; 127: 512-522
        • Liu Q.
        • Sundar K.
        • Mishra P.K.
        • et al.
        Helminth infection can reduce insulitis and type 1 diabetes through CD25- and IL-10-independent mechanisms.
        Infect Immun. 2009; 77: 5347-5358
        • Zaccone P.
        • Burton O.
        • Miller N.
        • et al.
        Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice.
        Eur J Immunol. 2009; 39: 1098-1107
        • Saunders K.A.
        • Raine T.
        • Cooke A.
        • et al.
        Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection.
        Infect Immun. 2007; 75: 397-407
        • Zaccone P.
        • Fehervari Z.
        • Jones F.M.
        • et al.
        Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes.
        Eur J Immunol. 2003; 33: 1439-1449
        • Cooke A.
        • Tonks P.
        • Jones F.M.
        • et al.
        Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice.
        Parasite Immunol. 1999; 21: 169-176
        • Pearson D.J.
        • Taylor G.
        The influence of the nematode Syphacia oblevata on adjuvant arthritis in the rat.
        Immunology. 1975; 29: 391-396
        • Rocha F.A.
        • Leite A.K.
        • Pompeu M.M.
        • et al.
        Protective effect of an extract from Ascaris suum in experimental arthritis models.
        Infect Immun. 2008; 76: 2736-2745
        • Salinas-Carmona M.C.
        • de la Cruz-Galicia G.
        • Perez-Rivera I.
        • et al.
        Spontaneous arthritis in MRL/lpr mice is aggravated by Staphylococcus aureus and ameliorated by Nippostrongylus brasiliensis infections.
        Autoimmunity. 2009; 42: 25-32
        • Osada Y.
        • Shimizu S.
        • Kumagai T.
        • et al.
        Schistosoma mansoni infection reduces severity of collagen-induced arthritis via down-regulation of pro-inflammatory mediators.
        Int J Parasitol. 2009; 39: 457-464
        • Elliott D.E.
        • Li J.
        • Blum A.
        • et al.
        Exposure to schistosome eggs protects mice from TNBS-induced colitis.
        Am J Physiol Gastrointest Liver Physiol. 2003; 284: G385-G391
        • Elliott D.E.
        • Setiawan T.
        • Metwali A.
        • et al.
        Heligmosomoides polygyrus inhibits established colitis in IL-10-deficient mice.
        Eur J Immunol. 2004; 34: 2690-2698
        • Weinstock J.V.
        • Summers R.W.
        • Elliott D.E.
        Role of helminths in regulating mucosal inflammation.
        Springer Semin Immunopathol. 2005; 27: 249-271
        • Smith P.
        • Mangan N.E.
        • Walsh C.M.
        • et al.
        Infection with a helminth parasite prevents experimental colitis via a macrophage-mediated mechanism.
        J Immunol. 2007; 178: 4557-4566
        • Khan W.I.
        • Blennerhasset P.A.
        • Varghese A.K.
        • et al.
        Intestinal nematode infection ameliorates experimental colitis in mice.
        Infect Immun. 2002; 70: 5931-5937
        • La Flamme A.C.
        • Ruddenklau K.
        • Backstrom B.T.
        Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyelitis.
        Infect Immun. 2003; 71: 4996-5004
        • Sewell D.
        • Qing Z.
        • Reinke E.
        • et al.
        Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization.
        Int Immunol. 2003; 15: 59-69
        • Zheng X.
        • Hu X.
        • Zhou G.
        • et al.
        Soluble egg antigen from Schistosoma japonicum modulates the progression of chronic progressive experimental autoimmune encephalomyelitis via Th2-shift response.
        J Neuroimmunol. 2008; 194: 107-114
        • Gruden-Movsesijan A.
        • Ilic N.
        • Mostarica-Stojkovic M.
        • et al.
        Trichinella spiralis: modulation of experimental autoimmune encephalomyelitis in DA rats.
        Exp Parasitol. 2008; 118: 641-647
        • Walsh K.P.
        • Brady M.T.
        • Finlay C.M.
        • et al.
        Infection with a helminth parasite attenuates autoimmunity through TGF-beta-mediated suppression of Th17 and Th1 responses.
        J Immunol. 2009; 183: 1577-1586
        • Demirturk N.
        • Kozan E.
        • Demirdal T.
        • et al.
        Effect of parasitosis on allergic sensitization in rats sensitized with ovalbumin: interaction between parasitosis and allergic sensitization.
        Adv Ther. 2007; 24: 1305-1313
        • Michels C.
        • Goyal P.
        • Nieuwenhuizen N.
        • et al.
        Infection with Syphacia obvelata (pinworm) induces protective Th2 immune responses and influences ovalbumin-induced allergic reactions.
        Infect Immun. 2006; 74: 5926-5932
        • Hunter M.M.
        • Wang A.
        • McKay D.M.
        Helminth infection enhances disease in a murine TH2 model of colitis.
        Gastroenterology. 2007; 132: 1320-1330
        • Pinelli E.
        • Brandes S.
        • Dormans J.
        • et al.
        Infection with the roundworm Toxocara canis leads to exacerbation of experimental allergic airway inflammation.
        Clin Exp Allergy. 2008; 38: 649-658
        • Strait R.T.
        • Morris S.C.
        • Smiley K.
        • et al.
        IL-4 exacerbates anaphylaxis.
        J Immunol. 2003; 170: 3835-3842
        • Leonardi-Bee J.
        • Pritchard D.
        • Britton J.
        Asthma and current intestinal parasite infection: systematic review and meta-analysis.
        Am J Respir Crit Care Med. 2006; 174: 514-523
        • Feary J.
        • Britton J.
        • Leonardi-Bee J.
        Atopy and current intestinal parasite infection: a systematic review and meta-analysis.
        Allergy. 2011; 66: 569-578
        • Gale E.A.
        A missing link in the hygiene hypothesis?.
        Diabetologia. 2002; 45: 588-594
        • Huang S.L.
        • Tsai P.F.
        • Yeh Y.F.
        Negative association of Enterobius infestation with asthma and rhinitis in primary school children in Taipei.
        Clin Exp Allergy. 2002; 32: 1029-1032
        • Jarrett E.E.
        • Kerr J.W.
        Threadworms and IgE in allergic asthma.
        Clin Allergy. 1973; 3: 203-207
        • Bahceciler N.N.
        • Ozdemir C.
        • Kucukosmanoglu E.
        • et al.
        Association between previous enterobiasis and current wheezing: evaluation of 1018 children.
        Allergy Asthma Proc. 2007; 28: 174-182
        • Cook G.C.
        Enterobius vermicularis infection.
        Gut. 1994; 35: 1159-1162
        • Lohiya G.S.
        • Tan-Figueroa L.
        • Crinella F.M.
        • et al.
        Epidemiology and control of enterobiasis in a developmental center.
        West J Med. 2000; 172: 305-308
        • Pedersen C.B.
        • Gotzsche H.
        • Moller J.O.
        • et al.
        The Danish Civil Registration System.
        Dan Med Bull. 2006; 53: 441-449
        • Hviid A.
        • Melbye M.
        Measles-mumps-rubella vaccination and asthma-like disease in early childhood.
        Am J Epidemiol. 2008; 168: 1277-1283
        • Andersen T.F.
        • Madsen M.
        • Jorgensen J.
        • et al.
        The Danish National Hospital Register.
        Dan Med Bull. 1999; 46: 263-268
        • Jardine M.
        • Kokai G.K.
        • Dalzell A.M.
        Enterobius vermicularis and colitis in children.
        J Pediatr Gastroenterol Nutr. 2006; 43: 610-612
        • Alshishtawy M.M.
        • Abdella A.M.
        • Gelber L.E.
        • et al.
        Asthma in Tanta, Egypt: serologic analysis of total and specific IgE antibody levels and their relationship to parasite infection.
        Int Arch Allergy Appl Immunol. 1991; 96: 348-354
        • Alcasid M.L.
        • Chiaramonte L.T.
        • Kim H.J.
        • et al.
        Bronchial asthma and intestinal parasites.
        N Y State J Med. 1973; 73: 1786-1788
        • Carswell F.
        • Merrett J.
        • Merrett T.G.
        • et al.
        IgE, parasites and asthma in Tanzanian children.
        Clin Allergy. 1977; 7: 445-453
        • Carswell F.
        • Meakins R.H.
        • Harland P.S.
        Parasites and asthma in Tanzanian children.
        Lancet. 1976; 2: 706-707
        • Nascimento Silva M.T.
        • Andrade J.
        • Tavares-Neto J.
        [Asthma and ascariasis in children aged two to ten living in a low income suburb].
        J Pediatr (Rio J). 2003; 79: 227-232
        • Scrivener S.
        • Yemaneberhan H.
        • Zebenigus M.
        • et al.
        Independent effects of intestinal parasite infection and domestic allergen exposure on risk of wheeze in Ethiopia: a nested case-control study.
        Lancet. 2001; 358: 1493-1499
        • Calvert J.
        • Burney P.
        Ascaris, atopy, and exercise-induced bronchoconstriction in rural and urban South African children.
        J Allergy Clin Immunol. 2010; 125: 100-105
        • Loeffler W.
        Transient lung infiltrations with blood eosinophilia.
        Int Arch Allergy. 1956; 8: 54-59
        • Bager P.
        • Wohlfahrt J.
        • Kristensen B.
        • et al.
        Reply (correspondence).
        J Allergy Clin Immunol. 2010; 125: 768-769
        • Rodrigues L.C.
        • Newcombe P.J.
        • Cunha S.S.
        • et al.
        Early infection with Trichuris trichiura and allergen skin test reactivity in later childhood.
        Clin Exp Allergy. 2008; 38: 1769-1777
        • Wordemann M.
        • Diaz R.J.
        • Heredia L.M.
        • et al.
        Association of atopy, asthma, allergic rhinoconjunctivitis, atopic dermatitis and intestinal helminth infections in Cuban children.
        Trop Med Int Health. 2008; 13: 180-186
        • Hood C.
        Enterobius vermicularis.
        Practitioner. 1989; 233: 503
        • Magnussen P.
        Imported infectious diseases in patients at Blegdam's Hospital and the epidemic diseases department of Rigshospitalet, Copenhagen, during 1975–1986.
        Ugeskr Laeger. 1989; 151: 2509-2514
        • Fonager K.
        • Sorensen H.T.
        • Rasmussen S.N.
        • et al.
        Assessment of the diagnoses of Crohn's disease and ulcerative colitis in a Danish hospital information system.
        Scand J Gastroenterol. 1996; 31: 154-159
        • Nielsen G.L.
        • Sorensen H.T.
        • Pedersen A.B.
        • et al.
        Analyses of data quality in registries concerning diabetes mellitus—a comparison between a population based hospital discharge and an insulin prescription registry.
        J Med Syst. 1996; 20: 1-10
        • Moth G.
        • Vedsted P.
        • Schiotz P.O.
        National registry diagnoses agree with medical records on hospitalized asthmatic children.
        Acta Paediatr. 2007; 96: 1470-1473
        • Jess T.
        • Simonsen J.
        • Nielsen N.M.
        • et al.
        Enteric Salmonella or Campylobacter infections and the risk of inflammatory bowel disease.
        Gut. 2011; 60: 318-324
        • Hviid A.
        • Svanstrom H.
        • Frisch M.
        Antibiotic use and inflammatory bowel diseases in childhood.
        Gut. 2011; 60: 49-54
        • Croese J.
        • O'Neil J.
        • Masson J.
        • et al.
        A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors.
        Gut. 2006; 55: 136-137
        • Buening J.
        • Homann N.
        • von Smolinski D.
        • et al.
        Helminths as governors of inflammatory bowel disease.
        Gut. 2008; 57: 1182-1183
        • Broadhurst M.J.
        • Leung J.M.
        • Kashyap V.
        • et al.
        IL-22+ CD4+ T cells are associated with therapeutic trichuris trichiura infection in an ulcerative colitis patient.
        Sci Transl Med. 2010; 2 (60ra88)
        • Harnett W.
        • Harnett M.M.
        Helminth-derived immunomodulators: can understanding the worm produce the pill?.
        Nat Rev Immunol. 2010; 10: 278-284